Enantiospecific complexation gas chromatography of nerve agents.  Isolation and properties of the enantiomers of ethyl N,N-dimethylphosphoramidocyanidate (tabun)

Degenhardt, Carla E. A. M.; Berg, G. R. Van Den; Jong, L.P.A. de; Benschop, H. P.; Genderen, J.L. van; Meent, Dory. Van de

doi:10.1021/ja00286a043

Cited by 30 publications

(14 citation statements)

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“…The MuAcChE-tabun complex exhibits an acyl-enzyme intermediate in the P R conformation, indicating that the enzyme reacted with the P S form of tabun ( Figure 6A). This observation is in agreement with the work of Degenhart, et al that shows AcChE is inhibited 6-fold more readily by P S -tabun relative to the P R isoform (43). Note, however, that hCE1 and AcChE exhibit acyl-enzyme intermediates with the opposite stereochemistry: P S for hCE1 and P R for AcChE ( Figure 6A).…”

Section: Comparison To Cholinesterase-nerve Agent Structuressupporting

confidence: 93%

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

et al. 2007

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The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 Å resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acylenzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10 4 -fold more lethal P S stereoisomer of soman relative to the P R form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to deadend organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure.The organophosphorus (OP) nerve agents sarin, soman, tabun, and VX are among the deadliest man-made chemicals (1). While the military use of OP nerve agents is widely banned, these compounds have been employed in recent decades by rogue states and terrorist groups. In 1988, Iraq employed weaponized sarin against its own Kurdish citizens in Halabja, a town adjacent to the Iranian border, killing an estimated 5,000 (2). Coordinated attacks on the Tokyo subway system by the Japanese Aum Shinrikyo cult in 1995 also employed sarin, killing 12 and injuring † This work was supported, in part, by NIH grants CA98468 and NS58089, and the American Lebanese Syrian Associated Charities. ‡ Protein Data Bank codes are 2HRQ for the hCE1-soman structure and 2HRR for the hCE1-tabun structure. *Corresponding Author: Matthew R. Redinbo, Ph.D., Department of Chemistry, CB #3290, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, (919)843-8910; Fax: (919)962-2388, redinbo@unc.edu. 1 Abbreviations: AcChE, Human acetylcholinesterase; BuChE, Human butyrylcholinesterase; CE, carboxylesterase; hCE1, Human carboxylesterase 1; HI-6, 1-(2-hydroxy-iminomethylpyridinium)-1-(4-carboxyamino)-pyridinium dimethylether dichloride; MuAcChE, Mus musculus acetylcholinesterase; OP, organophosphate; Ortho-7, 1,7-heptylene-bis-N,N′-2-pyridiniumaldoxime dichloride; PON1, human serum paraoxonase 1; rmsd, root mean square deviation; Sarin, methylethyl methylphosphonofluoridate; Soman, Tabun, ethyl N, TcAcChE, Torpedo californica acetylcholinesterase; VX, OP toxicity is thought to be mediated through the inhibition of human acety...

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Section: Comparison To Cholinesterase-nerve Agent Structuressupporting

confidence: 93%

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

et al. 2007

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“…Degenhardt et al reported that (−)-tabun is preferentially hydrolyzed by "phosphorylphosphatases" from rat plasma, resulting in enantiomeric excess (ee) of (+)-tabun up to 100%, albeit in low yield. On the other hand, "phosphorylphosphatases" from swine, guinea pig and human plasma showed only a slight preference for the hydrolysis of (+)-tabun, resulting in a slight enrichment of the (−)-enantiomer [19]. According to these findings the later eluting tabun peak of the present assay was assigned to (−)-tabun.…”

Section: Identification Of Enantiomerssupporting

confidence: 45%

“…Degenhardt et al [19] developed a procedure for the separation and quantification of tabun isomers, using a specially designed europium shift-reagent coated column for GC-MS/NPD (nitrogen phosphorus detector). This assay, however, did not lead to a complete baseline separation of the tabun enantiomers.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a sensitive gas chromatography–ammonia chemical ionization mass spectrometry method for the determination of tabun enantiomers in hemolysed blood and plasma of different species

Tenberken

Worek

Thiermann

et al. 2010

Journal of Chromatography B

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“…Bovine pancreas chymotrypsin has been shown to be enantioselective for the hydrolysis of the P(+) enantiomer of GA, allowing for the isolation of the P(–) enantiomer at up to 99% optical purity. 7 Racemic GA was incubated with α-chymotrypsin to determine the rate of hydrolysis of each enantiomer. By analogy, the enantiomer with the higher rate of hydrolysis can be assigned as the P(+) enantiomer of GA. Several aliquots were removed from the reaction mixture over the incubation period, and unreacted GA was extracted into hexane prior to injection onto the SFC with two WhelkO1 (SS) columns in tandem.…”

Section: Resultsmentioning

confidence: 99%

“…It has been demonstrated that rabbit plasma is highly enantioselective, with a marked preference for degrading the P(+) enantiomer of GB. 7 To determine the enantiospecific elution order of GB enantiomers, racemic GB was incubated with rabbit plasma and various reaction endpoints were collected. Extracted samples were injected onto the WhelkO1 (SS) column, and the results indicated enantioselective hydrolysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Chiral Separation of G‐type Chemical Warfare Nerve Agents via Analytical Supercritical Fluid Chromatography

Kasten¹,

Zulli

Jones

et al. 2014

Chirality

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Chemical warfare nerve agents (CWNAs) are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Undirected synthesis of G-type CWNAs produces stereoisomers of tabun, sarin, soman, and cyclosarin (GA, GB, GD, and GF, respectively). Analytical-scale methods were developed using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer for the separation, quantitation, and isolation of individual stereoisomers of GA, GB, GD, and GF. Screening various chiral stationary phases (CSPs) for the capacity to provide full baseline separation of the CWNAs revealed that a Regis WhelkO1 (SS) column was capable of separating the enantiomers of GA, GB, and GF, with elution of the P(+) enantiomer preceding elution of the corresponding P(–) enantiomer; two WhelkO1 (SS) columns had to be connected in series to achieve complete baseline resolution. The four diastereomers of GD were also resolved using two tandem WhelkO1 (SS) columns, with complete baseline separation of the two P(+) epimers. A single WhelkO1 (RR) column with inverse stereochemistry resulted in baseline separation of the GD P(–) epimers. The analytical methods described can be scaled to allow isolation of individual stereoisomers to assist in screening and development of countermeasures to organophosphorus nerve agents. Chirality 26:817–824, 2014. © 2014 The Authors. Chirality published by John Wiley Periodicals, Inc.

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Enantiospecific complexation gas chromatography of nerve agents. Isolation and properties of the enantiomers of ethyl N,N-dimethylphosphoramidocyanidate (tabun)

Cited by 30 publications

References 0 publications

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

Development and validation of a sensitive gas chromatography–ammonia chemical ionization mass spectrometry method for the determination of tabun enantiomers in hemolysed blood and plasma of different species

Chiral Separation of G‐type Chemical Warfare Nerve Agents via Analytical Supercritical Fluid Chromatography

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Enantiospecific complexation gas chromatography of nerve agents. Isolation and properties of the enantiomers of ethyl N,N-dimethylphosphoramidocyanidate (tabun)

Cited by 30 publications

References 0 publications

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun,

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun,

Development and validation of a sensitive gas chromatography–ammonia chemical ionization mass spectrometry method for the determination of tabun enantiomers in hemolysed blood and plasma of different species

Chiral Separation of G‐type Chemical Warfare Nerve Agents via Analytical Supercritical Fluid Chromatography

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Product

Resources

About

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,